The present invention pertains generally to methods for inducing angiogenesis or collateral blood formation in a nonischemic skeletal muscle at risk of being affected by ischemia or a vascular occlusion, thereby maintaining or enhancing the level of perfusion of blood to the nonischemic skeletal muscle.
Vascular atherosclerotic disease, also known as peripheral arterial occlusive disease, is a major health problem, especially in the elderly. Its prevalence increases with age from 3% in individuals younger than 60 years old to over 20% in individuals 75 years or older. Treatment of patients suffering from peripheral arterial occlusive disease remains a considerable clinical issue despite advances in both surgical and percutaneous revascularization techniques. Many patients cannot benefit from these therapies because of the anatomic extent and distribution of arterial occlusion. In such patients, new therapeutic strategies have been sought to prevent the development of disabling symptoms related to ischemia such as claudication, resting pain and loss of tissue integrity in the distal limbs. The latter can ultimately lead to limb loss.
Angiogenesis, the growth of new blood vessels, is a complex process involving disruption of vascular basement membranes, migration and proliferation of endothelial cells, and subsequent blood vessel formation and maturation. Several mediators are known to elicit angiogenic responses, and administration of these mediators promotes revascularization of ischemic tissues. Vascular endothelial growth factor (VEGF) is one of the most specific of the known angiogenic mediators due to localization of its receptors almost exclusively on endothelial cells. Receptors for VEGF are upregulated under ischemic conditions, and the administration of recombinant VEGF augments development of collateral vessels and improves function in peripheral and myocardial ischemic tissue.
The presence of tissue ischemia at the time of administration of an angiogenic mediator has been considered an essential precondition to evoke the desired angiogenic effect. Whether an angiogenic mediator delivered to a normoperfused tissue prior to the occurrence of ischemia could stimulate the neovascularization process and preserve blood perfusion once ischemia develops remains an unsolved issue. Studies have shown, in principle, that it was possible to induce neovascularization in vivo using adenoviral vectors encoding VEGF in nonischemic retroperitoneal adipose tissue and nonischemic subcutaneous tissue. Another study demonstrated that in vivo angiogenesis could be induced by recombinant adenoviral vectors encoding either secreted or nonsecreted forms of acidic fibroblast growth factor (aFGF). Yet, another study failed to find that endothelial cell growth factor (ECGF) had any significant angiogenic effect on vessel growth in nonischemic tissue, yet stimulated vessel growth in ischemic tissue.
In addition to its importance in understanding the basic mechanisms involved in therapeutic angiogenesis, induction of angiogenesis in nonischemic skeletal muscle actually has clinical significance. There are many patients with peripheral arterial disease who do not have chronic ischemia but rather recurrent episodes of ischemia during physical activity. In one study, intermittent claudication was the only complaint in approximately 70% of patients with either aortoiliac or femoropopliteal atherosclerotic involvement.
In view of the foregoing, there exists a need for an effective method of inducing angiogenesis in a nonischemic skeletal muscle. The present invention provides such a method. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides a method for enhancing the level of perfusion of blood to a nonischemic skeletal muscle involving administering to a nonischemic skeletal muscle a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) a DNA encoding an angiogenic peptide. The present invention further provides a method of treating, either therapeutically or prophylactically, a nonischemic skeletal muscle at risk of suffering from ischemic damage. Also provided is a method of treating a nonischemic skeletal muscle at risk of being affected by a vascular occlusion through induction of collateral blood vessel formation in the nonischemic skeletal muscle. Finally, a method of inducing angiogenesis is provided by the present invention.